CN110590785B - Aminothiazole compound, preparation method thereof and application of aminothiazole compound in resisting enterovirus 71 - Google Patents
Aminothiazole compound, preparation method thereof and application of aminothiazole compound in resisting enterovirus 71 Download PDFInfo
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Abstract
The invention discloses an aminothiazole compound, a preparation method thereof and application of the aminothiazole compound in resisting enterovirus 71. Belongs to the technical field of medicine. Specifically, 2-chloro-1- (imidazo [1,2-a ] pyrimidine-3-yl) ethyl-1-ketone, 2-chloro-1- (imidazo [1,2-a ] pyridine-3-yl) ethyl-1-ketone or alpha-bromo acetophenone compounds and aromatic heterocyclic thiourea derivatives are used as raw materials, and a series of aminothiazole compounds are prepared through cyclization reaction. The aminothiazole compound has the activity of resisting enterovirus 71, has low toxicity to cells, can be developed as a novel anti-EV 71 medicament, and has wide application prospect.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an aminothiazole compound, a preparation method thereof and application of the aminothiazole compound in resisting enterovirus 71.
Background
The enterovirus is a non-enveloped single-stranded RNA virus of picornaviridae, and has high mutability. Enteroviruses include human enterovirus (A, B, C, D) and non-human enterovirus, whereas EV71 is assigned to human enterovirus. The EV71 virus can be divided into three genotypes (A, B, C), and the three genotypes can be subdivided into eleven subtypes according to the sequence difference in the structural protein VP 1. Genotype A contained only the elite strain (BrCr), and genotypes B and C each contained five subtypes (B1-B5, C1-C5).
The hand-foot-and-mouth diseases which cause serious threats to the life health of infants are mainly caused by EV71 and CA 16. The hand-foot-mouth disease can cause acute infectious diseases mainly characterized by fever, rash, herpes, herpangina and the like of hands, feet, oral cavity and the like, and is frequently seen in infants under the age of 5. The hand-foot-and-mouth disease caused by EV71 is more serious and is often closely related to nervous system diseases, such as meningitis and Japanese encephalitis, and even death can be caused. At present, medicines capable of effectively treating the hand-foot-and-mouth disease are still lacking, and symptomatic and supportive therapies are mainly adopted clinically for treating the hand-foot-and-mouth disease. In recent years, outbreaks of hand-foot-and-mouth disease are frequently reported, particularly in the sub-pacific region, so that designing and synthesizing a series of novel effective EV71 inhibitors is urgent.
Depending on the viral replication cycle, current drugs for treating EV71 are mainly focused on the following targets: 1. the capsid protein inhibitor, Pleconaril, is a capsid protein binding molecule that has been shown to have a broad spectrum of activity against rhinoviruses and enteroviruses, primarily by interfering with the capsid receptor binding site to inhibit viral attachment to host cells. 2. The 3C protease inhibitor has a highly conserved gene sequence for coding the 3C protease, for example, the potential antiviral inhibitor against the Lupintrivir designed according to the 3C protease has a good clinical effect, and the inhibitor developed based on the structure is also reported. 3. Host factor inhibitors such as PIK93 and GW5074 targeting PI4KB, 25-hydroxycholesterol targeting OSBP and the like are mainly characterized by lower drug resistance and have good application prospect.
Although EV71 small-molecule inhibitors with different structures are reported, few therapeutic drugs are really applied to clinical research, so that the synthesis of a series of EV71 small-molecule inhibitors with novel structural frameworks is necessary.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide an aminothiazole compound shown as the following general formula (I), wherein the aminothiazole compound has the activity of resisting enterovirus 71, can be developed as a novel anti-EV 71 medicament and has wide application prospect.
Another object of the present invention is to provide a method for preparing aminothiazole compounds represented by the following general formula (I).
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
in a first aspect, there is provided an aminothiazole compound represented by the general formula (I) or a pharmacologically or physiologically acceptable salt thereof,
wherein the content of the first and second substances,
R1is composed of
R2Is composed of
Preferably, the present invention provides compounds as shown in table 1 below:
TABLE 1
Still further, the present invention provides the following compounds: n- (2-bromophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-1), N- (2-fluorophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-4), N- ([1,1' -biphenyl ] -4-yl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-9), N- (2-bromo-4-methylphenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-11), 4- (imidazo [1,2-a ] pyrimidin-3-yl) -N-phenethyl-2-amine (I-18), 4- (imidazo [1,2-a ] pyrimidin-3-yl) -N- (quinolin-2-yl) thiazol-2-amine (I-20).
According to the invention, through in vitro anti-EV 71 activity experiments, the aminothiazole compound can be used for preparing an anti-enterovirus 71 medicament.
In a second aspect, the present invention provides the use of any one of the above aminothiazole compounds or a pharmacologically or physiologically acceptable salt thereof for the preparation of a medicament against the enterovirus type 71.
In a third aspect, there is provided a pharmaceutical composition against enterovirus 71, comprising the above aminothiazole compound or a pharmacologically or physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
In a fourth aspect, there is provided a process for preparing an aminothiazole compound represented by the general formula (I), which comprises the steps of: refluxing aromatic heterocyclic thiourea compound and alpha-halogenated aromatic ketone compound (such as 2-chloro-1- (imidazo [1,2-a ] pyrimidine-3-yl) ethyl-1-ketone, 2-chloro-1- (imidazo [1,2-a ] pyridine-3-yl) ethyl-1-ketone or alpha-bromoacetophenone compound) in ethanol overnight to obtain aminothiazole derivative,
R1is any one of substituted benzene ring, aromatic heterocyclic ring or substituted double benzene ring group; r2Is any one of aromatic heterocyclic ring or substituted benzene ring group.
Preferably, the ratio of the amount of the aromatic heterocyclic thiourea compound to the amount of the α -haloaromatic ketone compound in the preparation method of the aminothiazole compound represented by the general formula (I) is 1: 1.
The aminothiazole compound shown in the general formula (I) can effectively inhibit the activity of EV71, has low toxicity to cells, and can be used for preparing anti-EV 71 medicines.
Detailed Description
The present invention is described in further detail below with reference to examples, which are provided only for illustration of the process of the present invention and are not intended to limit the remainder of the disclosure in any way.
[ example 1 ] preparation of aromatic heterocyclic thiourea derivatives with substituent R
The aromatic heterocyclic thiourea derivative with R is synthesized by the reaction shown in the following formula i.
Taking the preparation of 1- (2, 6-dibromophenyl) thiourea 2m as an example, the steps are as follows: ammonium thiocyanate (273.0mg,3.6mmol) was dissolved in 15mL of acetone, followed by addition of benzoyl chloride (460.2mg,3.38mmol) and refluxing for 15 min. Cooled to room temperature, and 2, 6-dibromoaniline 1m (600mg,2.4mmol) was added and refluxed for 30 min. After cooling to room temperature, the mixture was poured into ice water and stirred for 30 min. Standing for two minutes, filtering by using a suction filter funnel, washing a precipitate with water, drying, dissolving the solid in 15mL of 10% NaOH solution, heating and stirring at 80 ℃ for 30min, cooling to room temperature, slowly dropwise adding 6N hydrochloric acid until the pH of the solution is 1-2, stirring for 30min, then adjusting the pH to 10 by using ammonia water, stirring for 5min, suction filtering, washing the solid with water, and drying. After dissolution in methanol, silica gel was added, stirred, spun dry and purified on a silica gel column using petroleum ether and ethyl acetate (V/V ═ 3/1) as mobile phase proportions to give the product 1- (2, 6-dibromophenyl) thiourea 2m (550mg, white solid) as starting material for reaction iv.
The preparation directions of other aromatic heterocyclic thiourea derivatives (2a-2t) with R are the same as the above.
[ example 2 ] band R2Preparation of alpha-chloroacetone derivatives
The R-band is synthesized by the reactions shown in the following formulas ii and iii2The alpha-chloroacetone derivative of (1).
Taking the preparation of 2-chloro-1- (imidazo [1,2-a ] pyrimidin-3-yl) ethan-1-one 5a as an example, the procedure was as follows: 2-aminopyrimidine 3a (1g, 10.5mmol) was weighed out and dissolved in 20mL of toluene, N-dimethyldimethylacetal (1.38g, 11.6mmol) was added and refluxed for 6 h. After TLC plate check reaction is complete, spin-dry to obtain crude N, N-dimethyl-N' - (pyrimidin-2-yl) formamidine 4 a. This was dissolved in 15mL of dichloromethane, 1, 3-dichloroacetone (2g, 15.8mmol) was added, and the mixture was refluxed overnight. After TLC monitoring the reaction was complete, it was concentrated and purified by passing through a silica gel column with a mobile phase ratio of petroleum ether and ethyl acetate (V/V-1/3). Finally, 700mg of 2-chloro-1- (imidazo [1,2-a ] pyrimidin-3-yl) ethan-1-one 5a was obtained as a yellow solid.
The compound 2-chloro-1- (imidazo [1,2-a ] pyridin-3-yl) ethan-1-one 5b was prepared as described above.
The α -bromoacetophenone compounds (5c-5d) were obtained by purchase.
[ example 3 ] preparation of aminothiazole Compounds of the present invention
Aminothiazole compounds are synthesized by the reactions shown in the following formulas iv and v.
1.0 equivalent of the aromatic heterocyclic thiourea derivative prepared in example 1 is taken and put into a 25mL single-neck flask, 8mL of absolute ethanol is added, and then 1.0 equivalent of the compound prepared or purchased in example 2 is added and refluxed overnight. And monitoring the reaction by TLC, and after the completion of the reaction is confirmed, separating and purifying by silica gel column chromatography to obtain the aminothiazole compound. The reaction formula is shown as the following formula:
R1is composed of
R2Is composed of
The above 6a-6x correspond to I-1 to I-24 in Table 1.
(1) Preparation of N- (2-bromophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-1) the compound 2a N- (2-bromophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine was prepared as an example with the following specific steps: 1- (2-bromophenyl) thiourea 1a (240mg, 1.0mmol, 1.0eq) was added to a 25mL single-neck flask containing 8mL absolute ethanol, 2-chloro-1- (imidazo [1,2-a ] pyrimidin-3-yl) ethan-1-one 5a (204mg, 1.0mmol, 1.0eq) was added, and refluxed overnight. After TLC monitoring the reaction was complete, silica gel was added to stir and purified through silica gel column using mobile phase ratio of petroleum ether and ethyl acetate (V/V ═ 1/3) to isolate pure compound I-1 as a yellow solid in 62% yield.
1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),9.45(d,J＝5.7Hz,1H),8.56(s,1H),8.19(s,1H),8.07(d,J＝7.6Hz,1H),7.68(d,J＝7.4Hz,1H),7.45-7.30(m,2H),7.18-6.98(m,2H).13C NMR(101MHz,DMSO-d6)δ165.86,150.08,148.45,139.82,139.26,134.93,133.99,133.60,128.95,125.79,123.87,119.62,115.54,109.68,105.00.
(2) Preparation of N- (3-bromophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-2)
With R1The aromatic heterocyclic thiourea derivative is 1- (3-bromophenyl) thiourea 1b, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 70% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),9.53(d,J＝1.8Hz,1H),8.61(q,J＝4.0Hz,1H),8.22(s,1H),8.16(s,1H),7.45(d,J＝3.2Hz,2H),7.31(t,J＝8.0Hz,1H),7.26-7.10(m,2H).13C NMR(101MHz,DMSO-d6)δ163.94,150.23,148.56,142.75,139.99,134.75,134.22,131.49,124.39,122.47,119.95,119.63,116.44,109.77,104.61.
(3) Preparation of N- (4-bromophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-3)
With R1The aromatic heterocyclic thiourea derivative is 1- (4-bromophenyl) thiourea 1c, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 65% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),9.46(d,J＝1.6Hz,1H),8.60(d,J＝2.1Hz,1H),8.22(s,1H),7.63(d,J＝8.8Hz,2H),7.53(d,J＝8.8Hz,2H),7.42(s,1H),7.27-7.23(m,1H).13C NMR(101MHz,DMSO-d6)δ164.07,150.19,148.57,140.64,140.03,134.79,134.29,132.32,119.66,119.51,113.22,109.93,104.44.
(4) Preparation of N- (2-fluorophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-4)
With R1The aromatic heterocyclic thiourea derivative is 1- (2-fluorophenyl) thiourea 1d, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 76% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.47(d,J＝1.8Hz,1H),8.59(d,J＝2.1Hz,1H),8.32(t,J＝7.8Hz,1H),8.21(s,1H),7.41(s,1H),7.34–7.16(m,3H),7.10-7.02(m,1H).13C NMR(101MHz,DMSO-d6)δ164.79,153.87,151.44,150.12,148.53,139.75,134.78,134.13,129.19,125.25,123.41,120.98,119.71,115.86,109.77,105.09.
(5) Preparation of N- (4-fluorophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-5)
With R1The aromatic heterocyclic thiourea derivative is 1- (4-fluorophenyl) thiourea 1e, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 76% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.48(d,J＝1.8Hz,1H),8.60(d,J＝2.1Hz,1H),8.21(s,1H),7.69-7.64(m,2H),7.38(s,1H),7.30–7.16(m,3H).13C NMR(101MHz,DMSO-d6)δ164.68,158.77,156.41,150.15,148.54,139.94,137.87,134.82,134.23,119.73,119.42,119.34,116.27,116.05,109.85,103.88.
(6) Preparation of 4- (imidazo [1,2-a ] pyrimidin-3-yl) -N- (4-methoxyphenyl) thiazol-2-amine (I-6)
With R1The aromatic heterocyclic thiourea derivative is 1- (4-methoxyphenyl) thiourea 1f, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 50% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.53(d,J＝1.8Hz,1H),8.60(d,J＝2.1Hz,1H),8.19(s,1H),7.54(d,J＝8.9Hz,2H),7.31(s,1H),7.25-7.21(m,1H),6.97(d,J＝9.0Hz,2H),3.75(s,3H).13C NMR(101MHz,DMSO-d6)δ165.40,154.98,150.10,148.49,140.03,134.89,134.77,134.04,119.78,114.87,109.79,103.11,55.71.
(7) Preparation of 4- (imidazo [1,2-a ] pyrimidin-3-yl) -N- (4-ethoxyphenyl) thiazol-2-amine (I-7)
With R1The aromatic heterocyclic thiourea derivative is 1g, R of 1- (4-ethoxyphenyl) thiourea2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 52% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.53(d,J＝1.7Hz,1H),8.59(d,J＝2.1Hz,1H),8.19(s,1H),7.52(d,J＝8.9Hz,2H),7.30(s,1H),7.25-7.20(m,1H),6.95(d,J＝8.9Hz,2H),4.00(q,J＝6.9Hz,2H),1.32(t,J＝6.9Hz,3H).13C NMR(101MHz,DMSO-d6)δ165.44,154.27,150.08,148.49,140.04,134.89,134.68,134.02,119.82,115.42,109.77,103.07,63.65,15.20.
(8) Preparation of 4- (imidazo [1,2-a ] pyrimidin-3-yl) -N- (4-trifluoromethylphenyl) thiazol-2-amine (I-8)
With R1The aromatic heterocyclic thiourea derivative is 1- (4-trifluoromethylphenyl) thiourea 1h, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 41% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),9.46(d,J＝6.9Hz,1H),8.66–8.54(m,1H),8.25(d,J＝1.6Hz,1H),7.85(d,J＝7.9Hz,2H),7.73(d,J＝7.8Hz,2H),7.50(d,J＝1.6Hz,1H),7.29-7.24(m,1H).13C NMR(101MHz,DMSO-d6)δ163.68,150.24,148.63,144.58,140.10,134.78,134.47,127.03,127.00,126.96,126.93,119.58,117.17,110.00,105.21.
(9) Preparation of N- ([1,1' -biphenyl ] -4-yl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-9)
With R1The aromatic heterocyclic thiourea derivative is 1- ([1,1' -biphenyl)]-4-yl) Thiourea 1i, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 36% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),9.54(d,J＝5.9Hz,1H),8.61(d,J＝1.8Hz,1H),8.24(s,1H),7.83–7.60(m,6H),7.47–7.40(m,3H),7.37–7.21(m,2H).13C NMR(101MHz,DMSO-d6)δ164.31,150.16,148.57,140.79,140.23,140.10,134.87,134.23,133.74,129.36,127.83,127.28,126.56,119.74,118.00,109.88,104.10.
(10) Preparation of 4- (imidazo [1,2-a ] pyrimidin-3-yl) -N-phenylthiazol-2-amine (I-10)
With R1The aromatic heterocyclic thiourea derivative is phenylthiourea 1j, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 69% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.54–9.49(m,1H),8.62–8.58(m,1H),8.21(s,1H),7.64(d,J＝7.9Hz,2H),7.40–7.34(m,3H),7.25–7.20(m,1H),7.00(t,J＝7.3Hz,1H).13C NMR(101MHz,DMSO-d6)δ164.55,150.16,148.53,141.34,140.02,134.83,134.14,129.64,122.13,119.75,117.67,109.81,103.90.
(11) Preparation of N- (2-bromo-4-methylphenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-11)
With R1The aromatic heterocyclic thiourea derivative is 1- (2-bromo-4-methylphenyl) thiourea 1k, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 78% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,CDCl3)δ9.52–9.48(m,1H),8.84–8.44(m,1H),8.08(s,1H),7.85(d,J＝8.3Hz,1H),7.75(s,1H),7.42(s,1H),7.15(d,J＝8.3Hz,1H),6.99–6.84(m,2H),2.32(s,3H).13C NMR(101MHz,CDCl3)δ164.90,149.52,140.75,135.34,134.62,133.74,133.33,129.15,119.36,113.58,108.83,103.68,20.50.
(12) Preparation of N- (2-bromo-4-fluorophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-12)
With R1The aromatic heterocyclic thiourea derivative is 1l, R of 1- (2-bromo-4-fluorophenyl) thiourea2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 48% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),9.44–9.40(m,1H),8.58–8.54(m,1H),8.18(s,1H),8.06–8.01(m,1H),7.70–7.65(m,1H),7.46–7.27(m,2H),7.18–7.14(m,1H).13C NMR(101MHz,DMSO-d6)δ166.41,159.85,157.41,150.08,148.45,139.83,136.10,134.90,133.98,126.02,120.53,120.27,119.60,116.02,115.80,109.69,104.76.
(13) Preparation of N- (2, 6-dibromophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-13)
With R1The aromatic heterocyclic thiourea derivative is 1- (2, 6-dibromophenyl) thiourea 1m, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 52% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.35(s,1H),8.53(s,1H),8.13(s,1H),7.82(d,J＝3.5Hz,2H),7.18(d,J＝66.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ167.55,150.10,148.38,140.21,138.22,134.68,133.82,133.45,130.80,125.04,119.54,109.52,104.23.
(14) Preparation of 4- (imidazo [1,2-a ] pyrimidin-3-yl) -N- (2,4, 6-tribromophenyl) thiazol-2-amine (I-14)
With R1The aromatic heterocyclic thiourea derivative is 1- (2,4, 6-tribromophenyl) thiourea 1n, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the object compound, the product prepared by the method described in reference (1)As a yellow solid, yield was 38%.
1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),9.32(d,J＝5.7Hz,1H),8.55(d,J＝1.9Hz,1H),8.21–8.03(m,3H),7.30(s,1H),7.16–7.10(m,1H).13C NMR(101MHz,DMSO-d6)δ166.98,150.11,148.41,135.45,134.61,133.88,125.61,121.32,119.46,109.58,104.62.
(15) Preparation of N- (2, 6-difluoro-4-iodophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-15)
With R1The aromatic heterocyclic thiourea derivative is 1- (2, 6-difluoro-4-iodophenyl) thiourea 1o, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 52% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),9.33–9.30(m,1H),8.57–8.53(m,1H),8.13(s,1H),7.73(d,J＝7.4Hz,2H),7.36(s,1H),7.17–7.13(m,1H).13C NMR(101MHz,DMSO-d6)δ166.10,158.58,156.03,150.18,148.43,139.92,134.57,133.92,122.06,121.81,119.40,109.67,105.34.
(16) Preparation of N- (2, 6-dichloro-4-methylphenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine (I-16)
With R1The aromatic heterocyclic thiourea derivative is 1- (2, 6-dichloro-4-methylphenyl) thiourea 1p, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 45% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,CDCl3)δ9.48–9.37(m,1H),8.59–8.44(m,1H),8.03(s,1H),7.82(s,1H),7.31(t,J＝8.5Hz,1H),7.17(d,J＝8.3Hz,1H),6.97–6.79(m,2H),2.41(s,3H).13C NMR(101MHz,CDCl3)δ167.96,149.50,148.59,140.61,136.90,134.65,134.57,133.60,133.43,130.45,129.82,128.04,119.24,108.69,104.94,20.58.
(17) Preparation of 4- (imidazo [1,2-a ] pyrimidin-3-yl) -N- (2,4, 6-trichlorophenyl) thiazol-2-amine (I-17)
With R1The aromatic heterocyclic thiourea derivative is 1- (2,4, 6-trichlorophenyl) thiourea 1q, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 56% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),9.32–9.26(m,1H),8.56–8.52(m,1H),8.13(s,1H),7.85(s,2H),7.32(s,1H),7.14–7.12(m,1H).13C NMR(101MHz,DMSO-d6)δ166.80,150.14,148.41,134.60,133.91,132.52,129.35,119.42,109.61,104.86.
(18) Preparation of 4- (imidazo [1,2-a ] pyrimidin-3-yl) -N-phenethyl-2-amine (I-18)
With R1The aromatic heterocyclic thiourea derivative is 1-phenethylthiourea 1R, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 29% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,CDCl3)δ9.56–9.52(m,1H),8.54–8.51(m,1H),8.02(s,1H),7.39–7.32(m,2H),7.30–7.24(m,3H),6.92–6.88(m,1H),6.73(s,1H),5.79(s,1H).3.67(t,J＝6.9Hz,2H),3.04(t,J＝7.0Hz,2H).13C NMR(101MHz,CDCl3)δ169.75,149.42,148.53,140.65,138.47,134.90,133.19,128.80,126.76,119.68,108.71,102.02,46.94,35.44.
(19)4- (imidazo [1,2-a ]]Preparation of pyrimidin-3-yl) -N- (pyrimidin-2-yl) thiazol-2-amine (I-19) with R1The aromatic heterocyclic thiourea derivative is 1- (pyrimidine-2-yl) thiourea 1s, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 39% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),9.83(d,J＝4.7Hz,1H),8.80–8.42(m,3H),8.24(s,1H),7.61(s,1H),7.15(d,J＝49.5Hz,2H).13C NMR(101MHz,DMSO-d6)δ160.41,158.65,157.38,150.15,148.51,139.57,135.50,133.82,119.63,114.70,109.63,107.72.
(20)4- (imidazo [1,2-a ]]Preparation of pyrimidin-3-yl) -N- (quinolin-2-yl) thiazol-2-amine (I-20) with R1The aromatic heterocyclic thiourea derivative is 1- (quinoline-2-yl) thiourea 1t, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyrimidin-3-yl) ethan-1-one 5a, the title compound was prepared in 39% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,DMSO-d6)δ11.96(s,1H),9.75–9.72(m,1H),8.64–8.60(m,1H),8.33–8.20(m,2H),7.96–7.82(m,2H),7.71(t,J＝7.2Hz,1H),7.63(s,1H),7.43(t,J＝7.3Hz,1H),7.33–7.21(m,2H).13C NMR(101MHz,DMSO-d6)δ160.16,150.63,150.13,148.52,146.23,139.12,138.58,135.09,133.97,130.57,128.38,126.42,124.64,124.45,119.85,113.22,109.61,107.68.
(21) N- (2-bromophenyl) -4- (imidazo [1, 2-a)]Preparation of pyridin-3-yl) thiazol-2-amine (I-21) with R1The aromatic heterocyclic thiourea derivative is 1- (2-bromophenyl) thiourea 1b, R2The substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1, 2-a)]Pyridin-3-yl) ethan-1-one 5b, the title compound was prepared in 45% yield as a yellow solid according to the procedure in (1).
1H NMR(400MHz,CDCl3)δ9.08(d,J＝7.0Hz,1H),8.15–8.11(m,1H),7.94(s,2H),7.66(d,J＝9.1Hz,1H),7.61–7.57(m,1H),7.38–7.31(m,1H),7.24–7.16(m,1H),6.98–6.90(m,1H),6.89–6.81(m,2H).13C NMR(101MHz,CDCl3)δ163.82,146.08,141.47,137.92,132.88,128.56,126.49,124.64,123.84,120.63,118.73,117.70,112.84,112.59,103.64.
(22) Preparation of N- (2-bromo-4-methylphenyl) -4- (imidazo [1,2-a ] pyridin-3-yl) thiazol-2-amine (I-22)
With R1The aromatic heterocyclic thiourea derivative is 1- (2-bromo-4-methylphenyl) thiourea 1k, and the R2 substituted alpha-chloroacetone derivative is 2-chloro-1- (imidazo [1,2-a ]]Pyridin-3-yl) ethan-1-one 5b, the title compound prepared according to the procedure in (1), the product being yellowA colored solid in 37% yield.
1H NMR(400MHz,CDCl3)δ9.09(d,J＝7.0Hz,1H),8.14–7.87(m,2H),7.79(s,1H),7.66(d,J＝9.0Hz,1H),7.42(s,1H),7.26–7.19(m,1H),7.15(d,J＝8.3Hz,1H),6.87–6.83(m,2H),2.32(s,3H).13C NMR(101MHz,CDCl3)δ164.51,146.06,141.48,135.47,134.25,133.24,132.79,129.16,126.53,124.58,120.69,119.18,117.69,113.27,112.54,103.25,20.49.
(23) Preparation of 4- (4-bromophenyl) -N- (2,4, 6-trichlorophenyl) thiazol-2-amine (I-23)
With R1The aromatic heterocyclic thiourea derivative is 1- (2,4, 6-trichlorophenyl) thiourea 1q, R2The substituted α -bromoacetone derivative was 2-bromo-1- (4-bromophenyl) ethan-1-one 5c, and the title compound was prepared in 56% yield as a white solid according to the procedure in (1).
1H NMR(400MHz,CDCl3)δ8.50(s,1H),7.58(d,J＝8.2Hz,2H),7.50–7.35(m,4H),6.78(s,1H).13C NMR(101MHz,CDCl3)δ170.68,139.36,138.75,136.93,136.68,134.00,132.84,125.79,109.70.
(24) Preparation of 4- (4-methoxyphenyl) -N- (2,4, 6-trichlorophenyl) thiazol-2-amine (I-24)
With R1The aromatic heterocyclic thiourea derivative is 1- (2,4, 6-trichlorophenyl) thiourea 1q, R2The substituted α -bromoacetone derivative was 2-bromo-1- (4-methoxyphenyl) ethan-1-one 5d, and the title compound was prepared in 52% yield as a white solid according to the procedure in (1).
1H NMR(400MHz,CDCl3)δ9.12(s,1H),7.59(d,J＝8.7Hz,2H),7.39(d,J＝6.5Hz,2H),6.76(d,J＝8.7Hz,2H),6.61(d,J＝6.5Hz,1H),3.81(s,3H).13C NMR(101MHz,CDCl3)δ167.48,159.29,151.05,134.87,134.76,132.91,128.81,127.38,113.64,101.04,55.25.
The chemical structures of the target compounds I-1 to I-24 of the present invention synthesized above are shown in Table 1.
[ example 4 ] aminothiazole Compounds bioactivity test
(1) Aminothiazole compounds have anti-EV 71 activity in vitro:
first, a mixture of EV71 virus and different dilutions of the drug was added to a 96-well plate confluent with RD cells at an area ratio of 80%, with 8 replicate wells per dilution. After the cells of the virus control group are completely diseased after being cultured for 24-48 hours at the constant temperature of 37 ℃, 20 mu L of MTS/PMS mixed solution is added, and the cells are continuously cultured for 4 hours at the constant temperature of 37 ℃. OD was measured at 490nm using a microplate reader. Inhibition ratio (%) of compound [1- (E-N)/(P-N)]X 100, wherein "E" represents the OD value of the experimental group, "P" represents the OD value of the positive control group, and "N" represents the OD value of the negative control group. The degree of cytopathic effect can reflect the degree of virus inhibition by the drug. Median inhibitory concentration (EC)50) Is an index of antiviral activity.
(2) Aminothiazole compound cytotoxicity assay:
the Cell Counting Kit-8 is CCK-8 Kit for short, and is a rapid high-sensitivity detection Kit widely applied to Cell proliferation and cytotoxicity based on WST-8 (chemical name: 2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfophenyl) -2H-tetrazole monosodium salt). The working principle is as follows: in the presence of an electron coupling agent, it is reduced by mitochondrial dehydrogenases to produce a highly water-soluble orange-yellow formazan product (formazan). The shade of color is proportional to the proliferation of cells and inversely proportional to cytotoxicity. OD was measured using a microplate reader at 450nM wavelength, indirectly reflecting the number of viable cells.
First, different dilutions of the drug were added after 24 hours to 96-well plates confluent with RD cells. After culturing for 8-24 hours at the constant temperature of 37 ℃, 20 mu L of MTS/PMS mixed solution is added, and the culture is continued for 4 hours at the constant temperature of 37 ℃. OD at 450nm was measured with a microplate reader. Inhibition ratio (%) of compound [1- (E-N)/(P-N)]X 100, wherein "E" represents the OD value of the experimental group, "P" represents the OD value of the positive control group, and "N" represents the OD value of the negative control group. Median inhibitory concentration (CC)50) Is an indicator of compound cytotoxicity.
The invention uses Envir oxime as control, checks the cytotoxicity and anti-EV 71 activity of 24 synthesized compounds, calculates the selectivity index SI of the compounds, and the result is shown in Table 2.
TABLE 2 results of anti-EV 71 activity and cytotoxicity of compound I1-24 of interest synthesized in the present invention
| Compounds | EC50(μM) | CC50(μM) | SI(EC50/CC50) |
| I-1 | 11.194 | >89.548 | >8.0 |
| I-2 | NA | 167.902 | - |
| I-3 | 44.774 | 179.096 | 4.0 |
| I-4 | 3.346 | 60.224 | 18.0 |
| I-5 | NA | 535.320 | - |
| I-6 | 51.541 | >51.541 | >1.0 |
| I-7 | 37.048 | 268.464 | 7.2 |
| I-8 | 69.185 | >369.434 | >5.3 |
| I-9 | 5.322 | 56.182 | 10.6 |
| I-10 | NA | >568.150 | - |
| I-11 | 10.787 | 56.182 | 5.2 |
| I-12 | 42.710 | 170.839 | 4.0 |
| I-13 | 73.887 | 100.819 | 1.4 |
| I-14 | 15.722 | 314.442 | 20.0 |
| I-15 | 27.459 | >27.459 | >1 |
| I-16 | 33.222 | 177.183 | 5.3 |
| I-17 | 21.008 | >420.165 | 20.0 |
| I-18 | 6.482 | 122.303 | 18.9 |
| I-19 | NA | >564.360 | - |
| I-20 | 7.102 | >483.933 | >68.1 |
| I-21 | 22.446 | >448.937 | >20.0 |
| I-22 | 86.517 | >432.586 | >5.0 |
| I-23 | NA | >383.530 | - |
| I-24 | NA | >432.126 | - |
| Enweioxime | 0.140 | 28.000 | 200.0 |
The above experimental results show that: most of the aminothiazoles synthesized have better anti-EV 71 activity, such as compound I-1 (EC)50＝11.194μM,SI>8.0)、I-4(EC50＝3.346μM,SI＝18.0)、I-9(EC50＝5.322μM,SI＝10.6)、I-11(EC50＝10.787μM,SI＝5.2)、I-18(EC506.482 μ M, SI 18.9) and I-20 (EC)50＝7.102μM,SI>68.1), and especially compounds I-4, I-18 and I-20 all showed lower micromolar levels of anti-influenza virus activity and higher selectivity.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (4)
1. An aminothiazole compound or a pharmacologically or physiologically acceptable salt thereof, characterized in that the structure is represented by the general formula (I):
wherein, the aminothiazole compound is specifically a compound shown in a table 1:
TABLE 1
2. Aminothiazole compounds or pharmacologically or physiologically acceptable salts thereof according to claim 1, wherein said aminothiazole compound represented by the general formula (I) is: n- (2-bromophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine, N- (2-fluorophenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine, N- ([1,1' -biphenyl ] -4-yl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine, N- (2-bromo-4-methylphenyl) -4- (imidazo [1,2-a ] pyrimidin-3-yl) thiazol-2-amine, 4- (imidazo [1,2-a ] pyrimidin-3-yl) -N-phenethyl-2-amine, 4- (imidazo [1,2-a ] pyrimidin-3-yl) -N- (quinolin-2-yl) thiazol-2-amine.
3. Use of the aminothiazole compound according to claim 1 or 2 or a pharmacologically or physiologically acceptable salt thereof for the preparation of an anti-enterovirus 71 drug.
4. An anti-enterovirus 71 pharmaceutical composition comprising the aminothiazole compound according to claim 1 or 2 or a pharmacologically or physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
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